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01 Research Progress Summary DIGESTIVE DISEASES A. Molecular pathogenesis

1. Using a genome-wide shRNA screen in colorectal cancer (CRC) cells with mutations in APC and KRAS, the team identified a novel oncogenic candidate SLC25A22. SLC25A22 plays an important role in tumour metabolism in KRAS-mutant CRC by promoting biosynthesis of the nonessential amino acid aspartate. SLC25A22 protein and mRNA levels were independent prognostic markers associated with poor survival in KRAS-mutant CRC patients. 2. Whole genome sequencing has identified solute carrier family 12 member 5 (SLC12A5) as a novel amplification gene in colorectal cancer. SLC12A5 possessed oncogenic properties by promoting tumour proliferation and metastasis, and inhibiting cell apoptosis. SLC12A5 protein overexpression was found to be an independent prognostic factor associated with shortened survival in colorectal cancer patients. 3. Using methylated DNA immunoprecipitation array, the team identified Carbonic Anhydrase 4 (CA4) as a novel tumour suppressor gene silenced in colorectal cancer through promoter methylation. CA4 inhibited Wnt signalling pathway via WTAP–WT1–TBL1 axis, thereby suppressing colorectal cancer development. The team also found that methylation status of CA4 may serve as an independent biomarker for the recurrence of CRC. 4. Sequencing of fimH gene of Escherichia coli (E. coli) leads to the identification of α-hemolysin-positive (hly+) type 1 E.coli that contributes to adenomagenesis and CRC in human females. Hly+ type 1-E. coli were more prevalent in stools from females with adenoma and CRC and their abundance was correlated with poor survival. Feeding hly+ type 1-E. coli to female, but not male mice, promotes colorectal tumourigenesis. Thus, hly+ type 1-E. coli are candidate causative factors of CRC in human females and a biomarker for diagnosis of CRC. 5. Whole genome and transcriptome sequencing in a case of CRC leads to the discovery of a tumour-specific LACTB2-NCOA2 fusion originating from chromosomal rearrangement of chromosome 8. This fusion gene is present in 6.1% of CRC cases, and it disrupts tumour suppressive function of NCOA2, thereby leading to increased tumour growth.

Principal Investigator

Professor Jun Yu

Team

Joseph JY Sung, Francis KL Chan, Henry LY Chan, Justin CY Wu, Vincent WS Wong, Siew C Ng, Dennis CC Wong, Jessie Q Liang (Medicine & Therapeutics, Institute of Digestive Disease); Enders KW Ng, James YW Lau, Simon SM Ng, Philip WY Chiu (, Institute of Digestive Disease)

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Figure 2. Oncogene, 2016. 35, 6271-80. Whole genome sequencing revealed novel genes harbouring mutations in NAFLD-HCC mice that affect eight cancer signalling pathways. Among all mutated genes, Cel and Hras are of particular interest. Mutations in these two genes both have oncogenic effects with different mechanisms. B. Biomarkers and Cancer Screening Copyright © 2017 Elsevier 1. The team evaluated faecal microbial markers for clinical use in detecting CRC and advanced adenoma, including Fusobacterium nucleatum (Fn), Peptostreptococcus anaerobius (Pa) and Parvimonas micra (Pm). Among these bacteria, Fn emerged as a promising markers for CRC. The Fn, when combined with the faecal immunochemical test (FIT), showed superior sensitivity than FIT alone in detecting CRC in the same patient cohort. 2. MicroRNA microarray identified miR-20a as the one of the most up- regulated miRNA in CRC compared to adjacent normal tissues. The team analysed miR-20a in 595 faecal samples (198 CRCs, 199 adenomas, and 198 healthy controls) and found that miR-20a was significantly higher in C. Gastric cancer faecal samples from CRC patients. Hence, miR-20a level in faeces is a non-invasive biomarker for diagnosis of CRC. 1. Using bioinformatics tools, the team integrated somatic mutational profiles and clinicopathologic 3. The team performed a systematic analysis of microRNA profiles from 1765 information from 544 gastric cancers using previously published datasets, and redefined gastric cancer tumour samples from The Cancer Genome Atlas, including oesophageal, into regular (86.8%) and hypermutated (13.2%) subtypes. The team's analyses also uncovered 6 novel gastric, liver, pancreatic, colon and rectal cancers, and found that digestive recurrently mutated genes (XIRP2, NBEA, COL14A1, CNBD1, ITGAV and AKAP6) in the regularly- cancers of different tissue origins could be differentiated according to their mutated gastric cancer subtype. Finally, the team devised a novel mutational signature that predicts miRNA expression profiles. Moreover, the team identified novel microRNA patient prognosis in regularly-mutated gastric cancer. signatures that are associated with patient outcome in digestive cancers. 2. Methylated DNA immunoprecipitation array revealed that MDGA2 is hypermethylated in gastric cancer. MDGA2 exerted a potent tumour suppressive effect in gastric cancer by the induction of apoptosis and cell cycle arrest. Antitumour effect of MDGA2 was mediated through stabilising of DNA methyltransferase 1 associated protein 1, which activated p53/p21 signalling. MDGA2 methylation is an independent prognostic factor that predicts poor survival in with gastric cancer. 3. The team additionally identified novel tumour suppressor genes, RASSF10, RNF180 and GDF1 that are silenced in human gastric cancer by promoter methylation. Methylation status of these two genes was associated with poor survival of gastric cancer patients. 4. The team identified the miR-508-3p as a novel tumour suppressor microRNA in gastric cancer. miR- 508-3p negatively regulates the expression NFKB1 and RELA, major components of NF-κB oncogenic signalling, thereby inhibiting gastric cancer cell growth. 5. (H. pylori) infection is associated with gastritis and gastric cancer. The team discovered Figure 1. , 151, 945-60 Cancer cells consume glutamine (Gln), which can be used in that the antimicrobial peptide cathelicidin inhibit H. pylori growth, and cathelicidin knockout in mice resulted protein biosynthesis or biosynthetic pathways. In the paper in stronger H. pylori colonization and inflammation. Bioengineered Lactococcus lactis with cathelicidin by Wong et al., we discovered a novel oncogene, SLC25A22, expression suppressed H. pylori infection and may be used as a therapeutic agent for treatment of gastritis. which is critically important for glutamine metabolism in colon cancers with KRAS mutations. Targeting of SLC25A22 might be a novel strategy to inhibit the growth of KRAS- mutant colon cancers.

Copyright © 2017 Elsevier

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D. Non-Alcoholic Fatty Liver Disease (NAFLD)

1. Epidemiological data showed that obesity and NAFLD are associated with hepatocellular carcinoma (HCC) development. Whole-exome sequencing of chemically-induced HCC in genetically obese mice and wild-type lean mice liver identified mutations in Carboxyl ester lipase (Cel) gene and Harvey rat sarcoma virus oncogene 1 (Hras) genes. Mutations in Cel gene cause cholesteryl ester accumulation, leading to endoplasmic reticulum stress that consequently activated IRE1α/c-Jun N-terminal kinase (JNK)/c-Jun/activating protein-1 (AP-1) signalling cascade to promote liver cell growth. On the other hand, gain of function mutations in Hras promoted cell growth via activating MAPK and PI3K/Akt pathways. Thus, Cel and Hras have important functional roles in the development of NAFLD-HCC. 2. The team elucidated underlying role of CXC chemokine receptor 3 (CXCR3) in non-alcoholic steatohepatitis (NADH) development using CXCR3 knockout mice. CXCR3 knockout mice were remarkably resistant to both methionine-and-choline-deficient (MCD) diet and high-fat high- carbohydrate high-cholesterol (HFHC) diet-induced NASH. CXCR3 was found to be involved in mediating pro-inflammatory response, autophagosome-lysosome impairment and endoplasmic reticulum stress, which contributed to NASH development. 3. The team identified Ying Yang 1 (YY1) as an oncogenic factor in HCC. YY1 is a transcription factor whose binding motif was enriched in H3K27me3-occupied genes, including genes for fifteen tumour-suppressive miRNAs. H3K27me3 is a repressive marker and YY1 over-expression suppressed expression of these tumour suppressive miRNA, thereby activating NF-κB signalling in hepatocarcinogenesis. 4. The team unraveled RASSF10 as a tumour suppressor silenced in HCC by promoter methylation. Recognitions Adhesion genes PCR array revealed that the Matrix Metalloproteinase 2 (MMP2) was a downstream effector of RASSF10. Down-regulation of MMP2 by RASSF10 contributed to reduced cell invasion and Awards and Fellowships migration in HCC cell lines. Member’s Full Name Details E. Inflammatory Bowel Disease (IBD) Jun Yu Croucher Senior Research Fellowship for 2016-2017 Jun Yu Council Member, American Gastroenterology Association (AGA) Oncology, USA 1. IBD is an emerging GI disease in Asia, but little is known about disease progression. In a prospective population-based study, the team enrolled Jun Yu Chairman of Immunology Association 413 patients with IBD from 8 countries in Asia. The team found that disease Jun Yu Pao Yue-Kong Scholar Chair Professor, University progression in Asian patients was comparable with that of the West, and Henry LY Chan Fellowship of American Association for the Study of Liver Disease patients with Crohn's disease have a more severe disease progression and accelerated use of immunosuppressants. Simon SM Ng The Royal College of Surgeons of Edinburgh Medal 2. Targeted expression profiling of patients with Crohn's disease (CD), Simon SM Ng The Best Original Paper Award in 2015 by Surgical Practice ulcerative colitis (UC) and healthy controls identified KAT2B as the most Young Investigator Award by American Gastroenterology Association Digestive Disease Siew C Ng significantly down-regulated epigenetic regulator in IBD. KAT2B drives the Week, San Diego, USA expression of anti-inflammatory cytokine IL-10 via histone H4K5 acetylation. Siew C Ng Exemplary Teaching Award, Faculty of Medicine, CUHK Thus, decreased KAT2B expression led to repression of IL-10, resulting in Top Reviewer Award, Alimentary Pharmacology and Therapeutics (APT) from Editors unchecked innate and adaptive inflammatory responses in IBD. Siew C Ng of APT 3. The team investigated the interaction between miRNAs and IL-23/Th- Distinguished Research Paper Award for Young Investigators, Hong Kong College of 17 pathway in IBD using a mice model of chemically-induced colitis. RNA Siew C Ng microarray profiling identified CLDN8 as a novel target gene in IBD that was down-regulated in both human IBD and induced IBD in mice. The team further Siew C Ng Research Excellence Award, Chinese showed that miR-223 mediates crosstalk between IL-23/Th-17 pathway and CLDN8 expression by directly targeting CLDN8 3’UTR region. Targeting of the IL23/miR-233/CLDN8 axis may provide therapeutic strategies for IBD management. Appendix: Digestive Diseases LI KA SHING INSTITUTE OF HEALTH SCIENCES PROGRESS REPORT 2016 068 Appendix: Digestive Diseases 069 LI KA SHING INSTITUTE OF HEALTH SCIENCES PROGRESS REPORT 2016

Grants and Consultancy Full Name Project Title Funding Source Start Date End Date Amount of PI (dd/mm/yyyy) (dd/mm/yyyy) (HK$) Full Name Start Date End Date Amount Project Title Funding Source Jun Yu 腸道微生態與感染及代謝 National Basic Research RMB of PI (dd/mm/yyyy) (dd/mm/yyyy) (HK$) 2013 2017 (Co-PI) 的研究 Program 22,000,000 Innovation and Joseph Sung / Partner State Key Technology Commission – Macrophage- Jun Yu / Laboratory of Digestive 01/04/2016 31/03/2018 10,000,000 Myofi broblast-Transition Research Grants Council – Innovation and Jun Yu (Co- Francis Chan Diseases in Organ Fibrosis: Collaborative Research 01/01/2013 31/12/2016 8,800,000 Technology Fund PI) Molecular Mechanisms Fund Characterization of WNT2 and Clinical Implications in the Oesophageal Research Grants Council – Jun Yu Cancer Microenvironment: 01/01/2014 31/12/2016 736,128 Massively Parallel General Research Fund Sequencing of Plasma Research Grants Council - Prognostic and Henry LY Nucleic Acids for the Theme-based Research 2011 2016 31,999,000 Therapeutic Implications Chan (Co-PI) Molecular Diagnostics of Scheme Functional Cancers Characterization of Urgent Versus Early Squalene Epoxidase in Research Grants Council – Food and Health Bureau – Jun Yu 01/01/2016 31/12/2018 1,141,432 James YW Endoscopy in High Risk Promoting Fatty Liver General Research Fund Health and Medical 01/01/2014 31/12/2016 829,400 Lau Patients with Acute Upper Disease-associated Liver Research Fund Cancer Gastrointestinal Bleeding Elucidation of a Novel Endoscopy Photodynamic Therapy*(PDT) for Tumour Suppressor Gene Food and Health Bureau – James YW SK Yee Medical Inoperable Bile Duct 2014 2016 1,639,924 Jun Yu MAP9 in Regulating Health and Medical 01/01/2016 31/12/2018 1,195,728 Lau Foundation Chromosome Instability in Research Fund Cancers in Hong Kong Colon Cancer Chinese Patients Elucidation of a Novel Fecal Microbiota Tumour Suppressor Transplantation (FMT) Research Grants Council – for Severe Clostridium Jun Yu Gene Tripartite Motif 67 01/01/2017 31/12/2019 1,154,550 Hong Kong Society of General Research Fund Siew C Ng Diffi cile Infection (CDI): 01/06/2014 31/05/2016 300,000 (TRIM67) in Colorectal Gastroenterology Cancer A Randomised Study with Concurrent Stool The Liver Cancer Genome Jun Yu (Co- Research Grants Council - Microbiota Assessment Project: Translating PI), Henry LY Theme-based Research 2011 2016 45,000,000 Genetic Discoveries to A Prospective Study Chan (Co-PI) Scheme Clinical Benefi ts of Serial Interferon- gamma Release Assays State Key Laboratory of Shenzhen Virtual (IGRA) for the Diagnosis Food and Health Bureau – Cancer Biology (CUHK RMB Jun Yu University Park Support 2012 2017 of Tuberculosis (TB) Research Fund for the Joint Research Base in 500,000 Siew C Ng 01/01/2015 31/12/2017 750,000 Scheme Infection in Patients Control of Infectious Shenzhen) with Immune-mediated Diseases Microbe, Colorectal Infl ammatory diseases Jun Yu SH Ho Foundation 2012 2018 5,000,000 Cancer and Obesity (IMID) Treated with MicroRNA-based Biologics Detection of Colorectal Technology and Health economic research RMB Siew C Ng Abbvie Pharmaceutical 2015 2017 250,000 Jun Yu Cancer: Key Technology Innovation Project Fund, 2013 2016 in IBD 4,000,000 Development Project Shenzhen Investigators

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Full Name Full Name Project Title Funding Source Start Date End Date Amount Project Title Funding Source Start Date End Date Amount of PI (dd/mm/yyyy) (dd/mm/yyyy) (HK$) of PI (dd/mm/yyyy) (dd/mm/yyyy) (HK$) A Combined Phase PGE2-induced DNA 2/3, Double-Blind, Dennis CC Methylation in Gastric Research Grants Council – 01/10/2015 30/09/2018 852,552 Randomized, Placebo- Wong Cancer: Mechanisms and General Research Fund Controlled, Induction Therapeutic Implications and Maintenance Study Siew C Ng Gilead Pharmaceutical 2015 2017 1,000,000 新抑癌基因SCNN1B在胃 The National Natural Evaluating the Safety and Dennis CC RMB 癌中的功能機制和臨床應 Science Foundation of 01/01/2016 31/12/2018 Effi cacy of GS-5745 in Wong 170,000 用價值研究 China Subjects with Moderately to Severely Active Ulcerative Colitis Publications A Prospective Study on A. Journal Papers the Risk of Colorectal Research Grants Council – Siew C Ng Neoplasms in Individuals 01/01/2014 31/12/2016 1,039,239 General Research Fund 1. Bai AH, Wu WK, Xu LL, Wong SH, Go MY, Chan AW, Harbord M, Zhang SH, Chen MH, Wu JC, Chan MW, Chan with a Family History of MT, Chan FK, Sung JJ, Yu J, Cheng AS, Ng SC. Dysregulated lysine acetyltransferase 2B promotes infl ammatory Advanced Adenomas bowel disease pathogenesis through transcriptional repression of interleukin-10. Journal of Crohns & Colitis. Plasma DNA as a Platform Research Grants Council – Simon SM 2016; 10(6):726-34. Technology for Cancer Theme-based Research 01/01/2017 31/12/2021 40,000,000 Ng (Co-PI) 2. Chan AW, Yu SN, Yu YH, Tong JH, Wang L, Tin EK, Chong CC, Chan SL, Wong GL, Wong VW, Chan HL, Lai PB, Detection Scheme To KF. Steatotic hepatocellular carcinoma: a variant associated with metabolic factors and late tumour relapse. Prevalence and Histopathology. 2016; 69(6):971-84. Clinical Signifi cance 3. Chan HC, Wong VW, Wong GL, Tang W, Wu JC, Ng SC. Prevalence of hepatitis B and clinical outcomes in of Nonalcoholic Fatty infl ammatory bowel disease patients in a viral-endemic region. Bmc Gastroenterology. 2016; 16:100. Liver Disease in Patients Vincent WS with Type 2 Diabetes: Research Grants Council – 4. Jin Y, Tang SW, Li WL, Ng SC, Chan MW, Sung JJ, Yu J. Hemolytic E. coli promotes colonic tumorigenesis in 01/01/2014 31/12/2016 560,756 Wong A Prospective Cohort General Research Fund females. Cancer Research. 2016; 76(10):2891-900. Study Using Controlled 5. Li LL, Li C, Mao HT, Du ZF, Chan WY, Murray P, Luo B, Chan AT, Mok TS, Chan FK, Ambinder RF, Tao Q. Attenuation Parameter Epigenetic inactivation of the CpG demethylase TET1 as a DNA methylation feedback loop in human cancers. and Liver Stiffness Scientifi c Reports. 2016; 6:26591. Measurements 6. Li X, Liang Q, Liu W, Zhang N, Xu L, Zhang X, Zhang J, Sung JJ, Yu J. Ras association domain family member 10 Incidence of Non- suppresses gastric cancer growth by cooperating with GSTP1 to regulate JNK/c-Jun/AP-1 pathway. Oncogene. 2016; alcoholic Fatty Liver 35(19):2453-64. Disease and Advanced 7. Li XC, Wu WK, Xing R, Wong SH, Liu YX, Fang XD, Zhang YL, Wang MY, Wang JQ, Li L, Zhou Y, Tang SW, Peng Fibrosis in Patients with SL, Qiu KL, Chen LY, Chen KX, Yang HM, Zhang W, Chan MT, Lu YY, Sung JJ, Yu J. Distinct subtypes of gastric Vincent WS Type 2 Diabetes: A Research Grants Council – 01/01/2017 31/12/2019 658,050 cancer defi ned by molecular characterization include novel mutational signatures with prognostic capability. Cancer Wong Prospective Cohort Study General Research Fund Research. 2016; 76(7):1724-32. Using Paired Controlled Attenuation Parameter 8. Ng SC, Lau JY, Chan FK, Suen BY, Tse YK, Hui AJ, Leung-Ki EL, Ching JYL, Chan AW, Wong MC, Ng SS, To and Liver Stiffness KF, Wu JC, Sung JJ. Risk of advanced adenomas in siblings of individuals with advanced adenomas: a cross- Measurements sectional study. Gastroenterology. 2016; 150(3):608-16. Functional Liver Cancer 9. Ng SC, Zeng ZR, Niewiadomski O, Tang W, Bell S, Kamm MA, Hu P, de Silva HJ, Niriella MA, Udara WS, Ong D, Vincent WS Research Grants Council – Epigenomics: Exploiting Ling KL, Ooi CJ, Hilmi I, Goh KL, Ouyang Q, Wang YF, Wu KC, Wang X, Pisespongsa P, Manatsathit S, Aniwan Wong (Co- Collaborative Research 01/01/2015 31/12/2017 7,418,375 Epigenetic Vulnerabilities S, Limsrivilai J, Gunawan J, Simadibrata M, Abdullah M, Tsang SW, Lo FH, Hui AJ, Chow CM, Yu HH, Li MF, Ng PI) Fund for Therapeutics KK, Ching JY, Chan V, Wu JC, Chan FK, Chen MH, Sung JJ, Epi A-PCsC. Early course of infl ammatory bowel disease in a population-based inception cohort study from 8 countries in Asia and Australia. Gastroenterology. 2016; 150(1):86-95.

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10. Shen J, Tsoi H, Liang Q, Chu ES, Liu D, Yu AC, Chan TF, Li X, Sung JJ, Wong VW, Yu J. Oncogenic mutations 25. Klappan GG, Ng SC. Globalisation of infl ammatory bowel disease: perspectives from the evolution of and dysregulated pathways in obesity-associated hepatocellular carcinoma. Oncogene. 2016; 35(49):6271-80. infl ammatory bowel disease in the UK and China. The Lancet Gastroenterology & Hepatology. 2016; 1(4): 11. Wang KN, Liang QY, Li XX, Tsoi H, Zhang JW, Wang H, Go MY, Chiu PW, Ng EK, Sung JJ, Yu J. MDGA2 is a 307-16. novel tumour suppressor cooperating with DMAP1 in gastric cancer and is associated with disease outcome. 26. Ng SC, Leung WK, Shi HY, Li MK, Leung CM, Ng CK, Lo FH, Hui YT, Tsang SW, Chan YK, Loo CK, Chan KH, Gut. 2016; 65(10):1619-31. Hui AJ, Chow WH, Harbord M, Ching JY, Lee M, Chan V, Tang W, Hung IF, Ho J, Lao WC, Wong MT, Sze SF, 12. Wong CC, Qian Y, Li X, Xu J, Kang W, Tong JH, To KF, Jin Y, Li W, Chen H, Go MY, Wu JL, Cheng KW, Ng Shan EH, Lam BC, Tong RW, Mak LY, Wong SH, Wu JC, Chan FK, Sung JJ. Epidemiology of infl ammatory SS, Sung JJ, Cai Z, Yu J. SLC25A22 promotes proliferation and survival of colorectal cancer cells with KRAS bowel disease from 1981 to 2014: results from a territory-wide population-based registry in Hong Kong. mutations and xenograft tumor progression in mice via intracellular synthesis of aspartate. Gastroenterology. Infl ammatory Bowel Diseases. 2016; 22(8):1954-60. 2016; 151(5):945-60. e6. 27. Ng WK, Wong SH, Ng SC. Changing epidemiological trends of infl ammatory bowel disease in Asia. Intestinal 13. Wong SH, Ip M, Hawkey PM, Lo N, Hardy K, Manzoor S, Hui WW, Choi KW, Wong RY, Yung IM, Cheung CS, Research. 2016; 14(2):111-9. (Review) Lam KL, Kwong T, Wu WK, Ng SC, Wu JC, Sung JJ, Lee N. High morbidity and mortality of Clostridium diffi cile 28. Qian Y, Wong CC, Lai SC, Chen HR, He XK, Sun LM, Wu JG, Zhou JC, Yu J, Liu WL, Zhou DY, Si JM. A infection and its associations with ribotype 002 in Hong Kong. Journal of Infection. 2016; 73(2):115-22. retrospective study of pyogenic liver abscess focusing on Klebsiella pneumoniae as a primary pathogen in 14. Wong SH, Kwong TN, Chow TC, Luk AK, Dai RZ, Nakatsu G, Lam TY, Zhang L, Wu JC, Chan FK, Ng SS, Wong China from 1994 to 2015. Scientifi c Reports. 2016; 6:38587. MC, Ng SC, Wu WK, Yu J, Sung JJ. Quantitation of faecal Fusobacterium improves faecal immunochemical 29. Sano Y, Byeon JS, Li XB, Wong MC, Chiu HM, Rerknimitr R, Utsumi T, Hattori S, Sano W, Iwatate M, Chiu test in detecting advanced colorectal neoplasia. Gut. 2016; 312766. P, Sung J. Colorectal cancer screening of the general population in East Asia. Digestive Endoscopy. 2016; 15. Xing R, Li L, Chen L, Gao Z, Wang H, Li W, Cui J, Tian G, Liang Q, Yu J, Sung JJ, Luo G, Gao H, Xu X, Yang 28(3):243-9. (Review) H, Wang J, Zhang X, Wang JM, Huang J, Yu Y, Wang J, Lu Y. Copy number variations of HLA-I and activation 30. Shi HY, Chan FK, Leung WK, Li MK, Leung CM, Sze SF, Ching JY, Lo FH, Tsang SW, Shan EH, Mak LY, Lam of NKp30 pathway determine the sensitivity of gastric cancer cells to the cytotoxicity of natural killer cells. BC, Hui AJ, Chow WH, Wong MT, Hung IF, Hui YT, Chan YK, Chan KH, Loo CK, Ng CK, Lao WC, Harbord M, Oncogene. 2016; 35(20):2584-91. Wu JC, Sung JJ, Ng SC. Low-dose azathioprine is effective in maintaining remission in steroid-dependent 16. Xu LX, Li XX, Cai MY, Chen JN, Li XC, Wu WK, Kang W, Tong JN, To KF, Guan XY, Sung JJ, Chan FK, Yu ulcerative colitis: results from a territory-wide Chinese population-based IBD registry. Therapeutic Advances in J. Increased expression of Solute carrier family 12 member 5 via gene amplifi cation contributes to tumour Gastroenterology. 2016; 9(4):449-56. progression and metastasis and associates with poor survival in colorectal cancer. Gut. 2016; 65(4):635-46. 31. Tang SW, Wu WK, Li XC, Wong SH, Wong N, Chan MT, Sung JJ, Yu J. Stratifi cation of digestive cancers with 17. Yau TO, Wu CW, Tang CM, Chen YX, Fang JY, Dong YJ, Liang QY, Ng SS, Chan FKL, Sung JJ, Yu J. microRNA- different pathological features and survival outcomes by microRNA expression. Scientifi c Reports. 2016; 6:24466. 20a in human faeces as a non-invasive biomarker for colorectal cancer. Oncotarget. 2016; 7(2):1559-68. 32. Wang HL, Chao K, Ng SC, Bai AH, Yu Q, Yu J, Li MY, Cui Y, Chen MH, Hu JF, Zhang SH. Pro-infl ammatory 18. Yu J, Wu WK, Liang Q, Zhang N, He J, Li X, Zhang X, Xu L, Chan MT, Ng SS, Sung JJ. Disruption of NCOA2 miR-223 mediates the cross-talk between the IL23 pathway and the intestinal barrier in infl ammatory bowel by recurrent fusion with LACTB2 in colorectal cancer. Oncogene. 2016; 35(2):187-95. disease. Genome Biology. 2016; 17:58. 19. Zhang JW, Tsoi H, Li XX, Wang H, Gao J, Wang KN, Go MN, Ng SC, Chan FKL, Sung JJ, Yu J. Carbonic 33. Wong SH, Gao QY, Tsoi KK, Wu WK, Tam LS, Lee N, Chan FK, Wu JC, Sung JJ, Ng SC. Effect of immunosuppressive anhydrase IV inhibits colon cancer development by inhibiting the Wnt signalling pathway through targeting therapy on interferon gamma release assay for latent tuberculosis screening in patients with autoimmune the WTAP-WT1-TBL1 axis. Gut. 2016; 65(9):1482-93. diseases: a systematic review and meta-analysis. Thorax. 2016; 71(1):64-72. 20. Zhang L, Wu WK, Gallo RL, Fang EF, Hu W, Ling TK, Shen J, Chan RL, Lu L, Luo XM, Li MX, Chan KM, 34. Xu ZL, Zhang X, Lau JN, Yu J. C-X-C motif chemokine 10 in non-alcoholic steatohepatitis: role as a pro- Yu J, Wong VW, Ng SC, Wong SH, Chan FK, Sung JJ, Chan MT, Cho CH. Critical role of antimicrobial infl ammatory factor and clinical implication. Expert Reviews in Molecular Medicine. 2016; 18:e16. (Review) peptide cathelicidin for controlling Helicobacter pylori survival and infection. Journal of Immunology. 2016; 35. Han F, Sun LP, Liu S, Xu Q, Liang QY, Zhang Z, Cao HC, Yu J, Fan DM, Nie YZ, Wu KC, Yuan Y. Promoter 196(4):1799-809. methylation of RNF180 is associated with H.pylori infection and serves as a marker for gastric cancer and 21. Zhang X, Han JQ, Man K, Li XX, Du JH, Chu ES, Go MY, Sung JJ, Yu J. CXC chemokine receptor 3 promotes atrophic gastritis. Oncotarget. 2016; 7(17):24800-9. steatohepatitis in mice through mediating infl ammatory cytokines, macrophages and autophagy. Journal of 36. Huang TT, Kang W, Zhang B, Wu F, Dong YJ, Tong JH, Yang WQ, Zhou YH, Zhang L, Cheng AS, Yu J, To KF. Hepatology. 2016; 64(1):160-70. miR-508-3p concordantly silences NFKB1 and RELA to inactivate canonical NF-kappa B signaling in gastric 22. Ananthakrishnan AN, Shi HY, Tang W, Law CC, Sung JJ, Chan FK, Ng SC. Systematic review and meta-analysis: carcinogenesis. Molecular Cancer. 2016; 15:9. phenotype and clinical outcomes of older-onset infl ammatory bowel disease. Journal of Crohns & Colitis. 37. Kang W, Cheng AS, Yu J, To KF. Emerging role of Hippo pathway in gastric and other gastrointestinal cancers. 2016; 10(10):1224-36. World Journal of Gastroenterology. 2016; 22(3):1279-88. (Review) 23. Hirai HW, Tsoi KK, Chan JY, Wong SH, Ching JY, Wong MC, Wu JC, Chan FK, Sung JJ, Ng SC. Systematic review 38. Wu RN, Nakatsu G, Zhang X, Yu J. Pathophysiological mechanisms and therapeutic potentials of macrophages with meta-analysis: faecal occult blood tests show lower colorectal cancer detection rates in the proximal colon in non-alcoholic steatohepatitis. Expert Opinion on Therapeutic Targets. 2016; 20(5):615-26. (Review) in colonoscopy-verifi ed diagnostic studies. Alimentary Pharmacology & Therapeutics. 2016; 43(7):755-64. 39. Zhou YH, Huang TT, Cheng AS, Yu J, Kang W, To KF. The TEAD family and its oncogenic role in promoting 24. Ho J, Chan H, Wong SH, Wang MH, Yu J, Xiao ZG, Liu XD, Choi G, Leung CC, Wong WT, Li Z, Gin T, Chan MT, Wu tumorigenesis. International Journal of Molecular Sciences. 2016; 17(1):138. (Review) WK. The involvement of regulatory non-coding RNAs in sepsis: a systematic review. Critical Care. 2016; 20:383.

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